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A new consortium of investigators is seeking to uncover the mysteries of genetic variants and the role they play in human disease, while also upping the standards and resources for calling and interpreting variants.

The Clinical Genome Resource (ClinGen) program represents public, academic, and private institutions and is funded by grants from the National Institutes of Health. As part of its mission to improve genomic interpretation, the consortium is working to resolve interpretation differences of genetic variants among labs and clinicians.

An article featuring the ClinGen project in the New England Journal of Medicine explains that while scientists have discovered at least 80 million genetic variants in the human genome, their role in human health and disease for the most part has not been fully elucidated.

“We are very far from a world in which we can sequence patients’ genomes and easily interpret their risk of disease, even if patients carry a variant in a gene that is associated with a highly penetrant genetic disorder,” wrote the authors.

“Sequencing has revealed that there are potentially several million genetic variants per person,” added co-author Jonathan Berg, MD, PhD, an assistant professor in the genetics department at the University of North Carolina’s (UNC’s) School of Medicine and chair of ClinGen’s steering committee, in a statement issued by UNC Health Care and UNC School of Medicine.

“Right now there is a certain degree to which we can infer what those variants do, but most of them remain really beyond our understanding of how they are affecting human health, if at all,” said Berg.

Berg and his co-authors also decried inconsistencies in interpreting genetic data. Through ClinVar, a public database that houses approximately 170,000 genetic variants from labs worldwide, ClinGen researchers found that more than 118,000 unique variants had clinical interpretations, 11% by more than one lab. Yet 17% of variants interpreted by more than one lab were interpreted differently by the labs.

In addition, the authors discovered that supposedly disease-causing genetic variants have been misinterpreted in the literature. “Such errors have resulted from insufficient standards for defining the evidence required to link a variant to disease causation and our lack of information on common variation across many populations,” the article stated.

To help resolve these interpretation differences, ClinGen has been coordinating with labs around the globe to facilitate data sharing and help them adopt standards created by the American College of Medical Genetics and Genomics for interpreting genetic variants. “This collaboration has allowed laboratories to resolve differences in interpretation through
expert consensus and application of these standardized
methods,” according to the NEJM article.

According to Berg, ClinGen collaborators are working to make improvements to the ClinVar database.

ClinGen has its sights set on developing an informatics system to assist researchers in their review of genetic variants, and has also created a portal where patients can register and share their genetic and health information. “Known as GenomeConnect, the portal connects researchers, clinicians and patients to learn about the effects of genetics on human health and disease,” according to the statement from UNC Health Care and UNC School of Medicine.